Project: Abstract The proposal is truly translational, as it draws from clinical observation and moves towards rigorous quantification of biomarkers of cognitive impairment in both mouse models and patients. Such a study will serve as a model for studies of other neurodevelopmental disorders in our comprehensive Center. These biomarkers can then, in future studies, be directly related to gene expression. First, we will identify a mechanism-based electrophysiological biomarker of cognitive dysfunction and potential responsiveness to treatment in a genetically well-defined syndrome highly associated with ID. Standardized measures of cognition are limited in their ability to quantify subtle individual differences or to capture clinical heterogeneity that may inform prognosis and intervention. Our group has considerable expertise in the integration of EEG biomarkers with behavior to better characterize children with neurodevelopmental disorders. Second, we will perform parallel studies in mouse models, in order to validate and better understand the genetic basis of biomarker identified in humans and to begin to test treatments that may alter both the cell activation patterns and behavior in these mouse models. Specifically we will test how abnormal oscillations disrupt information flow in awake behaving animals, allowing us to directly link electrophysiological changes to cognition. Innovative methods to study electrophysiological markers in both mouse models and patients. The human EEG experiments in the Jeste Lab will make use of new analysis techniques to measure signal complexity and to quantify resting state spectral power from challenging populations. The mouse experiments will make use of custom-made high density electrophysiological recordings from hundreds of neurons with silicon probes targeted to multiple cortical regions. New attention-based multimodal set shifting task designed in the Golshani lab to record the activity of large neuronal populations during flexible decision making and attentional set shifting, a cognitive domain that is affected in the disorder. Finally, we will use a new generation of miniaturized microscopes to record the activity patterns of large populations of hippocampal neurons over days during learning, allowing us for the first time to follow population dynamics in the same group of neurons during learning and extinction. Importantly, these studies are rooted in gaining a new understanding of ID at a systems level with a desire to find convergence in mechanisms and evidence-based treatments for individuals with this heterogeneous group of disorder.